An acetazolamide based multimodal analgesic approach versus conventional pain management in patients undergoing laparoscopic living donor nephrectomy.

SUMMARY
Choice of an appropriate anaesthetic technique and adequate pain relief during laparoscopic living donor nephrectomy (LDN) is likely to make the procedure more appealing to kidney donors. Various analgesic regimens proposed to relieve pain after laparoscopic surgery include: opioids, non-opioid analgesics followed by opioids for the breakthrough pain and intra-peritoneal normal saline irrigation and instillation of local anaesthetics at surgical sites. Thorough literature review and medline search did not reveal any study where a combination of orogastric acetazolamide along with intraperitoneal saline irrigation and bupivacaine instillation techniques have been tried in these patients. In a prospective, double blind, randomized trial, eighty healthy adults undergoing LDN under general anaesthesia were enrolled to compare the efficacy of an acetazolamide based multimodal analgesic approach (Group A) with conventional pain management (Group B). Donors' demographics, intra-operative variables, early allograft function and recovery characteristics were evaluated for 72 hours. The primary end points were postoperative pain intensity on a visual analog scale and the incidence of shoulder tip pain (STP). The secondary end points included the latency of the rescue analgesia request rate, total analgesic consumption and patient satisfaction. Consistently lower mean pain scores were observed in Group A (p<0.03 for visceral pain). Frequency as well as the total dose of rescue analgesics administered was significantly less in Group A (p=0.001). Twelve patients (30.7%) in Group B complained of STP compared to three (7.5%) in Group A (p=0.025). Shoulder pain also presented earlier (8 hours versus 12 hours) and persisted for longer period in Group B (72 hours versus 48 hours, p 0.025). To conclude, a multimodal analgesic approach consisting a combination of orogastric acetazolamide, intraperito-neal saline irrigation and use of bupivacaine in the operated renal fossa, pfannenstiel incision and laparoscopic port sites provide significant reduction in postoperative pain after LDN.

Various analgesic regimens have been proposed to relieve pain after laparoscopy. These include: administration of oral opioids at regular intervals, nonop io id analgesics followed by opioids for the breakthrough pain and intravenousmorphine infusion pumps for patient-controlled analgesia. 5,9 Intraperitonealnormalsaline irrigation and instillation of local anaesthetics has been found to be effective in reducing the postoperative narcotic requirement. 12 Alternatively, carbonic anhydrase inhibitors have been used to prevent the formation of carbonic acid. 13,14 However, search for idealanalgesic regimens is stillon. Since the aetiology of post operative pain following laparoscopic living donor nephrectomy (LDN) is multi factorial and there is paucity of data on the multiple prong therapy in these patients. We planned this study to compare the analgesic efficacy of a combination of orogastric acetazolamide, intraperitoneal irrigation of normalsaline followed by instillation of bupivacaine in the operated renal fossa and bupivacaine infiltration at incision sites with the conventional care group, where only bupivacaine was infiltrated at incision sites in the patients undergoing laparoscopic donor nephrectomy. The primary end points of the study were postoperative pain intensity on a visual analogscale and the incidence of shoulder tip pain. The secondary end points included the latencyof the rescue analgesiarequest rate, total analgesic consumption and patient satisfaction.

Methods
Afterobtainingapprovalfrom the institutional ethics committee and written informed consent from the participants, this prospective, double blind, randomized trialwas conducted on eighty healthy renaldonors of either gender,ASA I-II, aged 18-55years undergoing laparoscopic donor nephrectomy under general anaesthesia from July 2005-September 2007. During preanaesthetic evaluation, the participants were madefamiliar with11point visual analogscale. ( where 0 is no pain and 10 is worst imaginable pain) 15 . We excluded patients withpre-existing neuromuscular disorders, shoulderpathology, chronic obstructive pulmonary disease, double renal artery, hypokalemia /hy-ponatremia /metabolic acidosis, sulfonamide allergy, diuretics orlithium therapy,analgesics/antiemetics intake in thelast 12hours. Donors undergoing removalof right kidney or patients in whom laparoscopicprocedure had to be converted to open nephrectomy were not evaluated.All the participants wereinstructed to fast for eight hours prior to surgery. Premedication consisted of oral ranitidine(150mg), metoclopramide(10mg)& diazepam (5mg) administered twohours prior to surgery.
Allparticipants were randomly allocated into two groups A & B, (n=40each group) to receive either of the two analgesic regimens. GroupA(multimodal analgesia care group) received orogastric acetazolamide through Ryle's tube soon after the induction of anaesthesia (5mg.kg -1 diluted in 10ml normalsaline followed by 10 ml saline flushing). Powdered sachets of 5, 10, 50and 100 mg acetazolamide were prepared with the help of microbalance for adequate dosing. At the completion of surgical procedure, 15-20 ml.kg -1 normalsalinewas usedfor theintraperitoneal irrigation.This was followed by local instillationof 1.5mg.kg -1 dose of 0.5% bupivacaine in the operated renal fossa and bupivacaine infiltration (15ml of 0.25%) at the organ retrieval incision site and laparoscopic port sites. In Group B (Conventional care group) only bupivacaine (15mlof 0.25%) was infiltratedat surgicalincision sites on the completion of procedure.
On the day of surgery, heart rate (HR), electrocardiography (ECG), arterial oxygen saturation (Sp O 2 ),non-invasive blood pressure (NIBP) and endtidal carbon dioxide (EtCO 2 ) were monitored continuously and recorded at an interval of 10 minutes till the end of surgery. General anaesthesia was induced with intravenous morphine sulphate (0.15mg.kg -1 ), sleep dose of propofol (2 to 2.5mg.kg -1 ) and vecuronium (0.1mg.kg -1 ) to facilitate endotrachealintubation. Anaesthesia was maintained with Datex Ohmeda Aesitva-5 anesthesia ventilator using 100% oxygen and isoflurane (0.5-2%) titrated to effect. After the induction of anaesthesia, a Ryle's tube was inserted orally andgastric contents were aspirated out.Acetazolamide 5mg.kg -1 diluted in 10ml normal saline was adminis-tered through Ryle's tube in Group A. Thereafter, donor was shifted to the modified flank position with the torso in a 45-degree lateral decubitus position for transperitoneal nephrectomy.Pneumoperitoneum was established by CO 2 insufflation limiting pressure to <15mmHg. The totalflowof carbondioxide insufflated for producing pneumopertioneum was recorded. Intravenous ondansetron (100µg.kg -1 ) and intravenous morphine 3mg was administered half an hour before theexpected completionof surgery in both groups. On the completion of procedure,neuromuscular blockade was reversed with intravenous neostigmine 50µg.kg -1 and atropine 20µg.kg -1 . Patients'were extubated on meeting thestandard criteria for extubationand shifted to renal post anaesthesia care unit (PACU). An anaesthesiologist who was not aware of the patients' group assignments recorded vitalsigns (heart rate, respiratory rate and non-invasive blood pressure), level of sedation, (assessed by the Modified Observers Assessment of Alertness/Sedation Score (OAA/S) 16 and intensity of pain (assessed by a linear Visual Analog Scale) 15 for the first 72 hours after completion of surgery. He recorded parietal and visceral pain at rest (supine),on movement (sitting up from supine) and after coughing. Shoulder pain was also evaluated. Pain assessments were done at 30 min, 2, 4, 8, 12, 24, 48 and 72 hours after shiftingthe patient to post anaesthesia care unit. Patients were requested to evaluate their overall postoperative pain management at the end of study period.
Rescue analgesia (intravenous injection of tramadol 1.5mg.kg -1 ) was given if VAS score was > 3. If the pain persisted even after 30 minutes of intravenous tramadoladministration, the single dose of intravenous pethidine 0.5-1mg.kg -1 was given (second rescue analgesic agent). The time from extubation of the patient to the administration of first dose of rescue analgesic was recorded. Total dose and frequency of administration of tramadol and pethidine during the postoperative period were noted. The incidence and severity of postoperative nausea & vomiting/retching and thefrequency ofadministration ofrescue antiemetics were also noted. Side effects attributable to the study drug were specifically observed & recorded. (allergic reactions, drowsiness, paresthesia).
Thenumber ofpatients required for thestudy were calculated to detect a difference of at least two pain scale units in aten point VAS. Atotal of 37 participants were needed to detect a significant difference between groups with a 0.05level and 80% power in two-sided test of hypothesis. Adjustingfor participants who may not complete the study, we enrolled 40 adults in each group. The demographic data and haemodynamic parameters were compared using independent t-test. Chisquare test was used to compare the descriptive data. Pain scores for the different pain components were compared using Mann Whitney 'U' test. The occurrence of postoperative emetic episodes, rescue antiemetic therapy and rescue analgesic therapy were analyzed with the Chi-square test or the Fisher Exact test whereappropriate. Thestatisticalanalysiswasperformed usingthe SPSSfor windowsversion 13.0. Statistical significance was defined as p = 0.05.All values were expressed as mean ± SD, median (IQR) or number (%).

Results
Amongst eighty adults enrolled,one patient in the conventional care group required surgical re-exploration for postoperative bleeding, hence hewas excluded from data analysis. Donor characteristics, perioperative haemodynamicvariables,meanEtCO 2, durationof pneumoperitoneum, duration of surgery, anaesthesia time, quantity of intravenous fluids administered intra-operatively were comparable in both the groups ( Table 1).
Comparison of postoperative parietaland visceral pain VAS scores at rest, during movement and on coughing are depicted in Fig 1 & 2. Pain evaluations done at specific time intervals of 0.5, 2, 4, 8, 12, 24, 48 and 72 hours after extubation revealed that parietal pain was dominant over thevisceral andshoulder pain in both the groups. However the intensity of pain was lesser on movement and coughing inmultimodalanalgesia group, especially duringthe first 12 postoperative hours. On adjusting for repeated analysis of same  variable over time, using the conservative bonferroni correction where p value of less than 0.006 was considered statistically significant,we found that at 48hr of interval the visceral pain at rest was less in GroupA as compared to the Group B.
Twelve patients (30.7%) in Group B complained of shouldertip pain(STP) comparedto 3patients (7.5%) in Group A. (p=0.025). Pain also presented earlier in conventionalcaregroup (8hours)thaninthe multimodal analgesia group (12 hours). Assessment of pain at 36 postoperative hoursindicated that 8(20.5%) patients in Group Bhad shoulder pain, whereas in GroupA, none of participantscomplained ofSTP (p= 0.025). The pain also persisted up to 72hours in Group B(five patients ; 12.8%) as compared to group A where only two patients complained of referred pain at 48 hours ( Table 2). The mean intensity ofshoulder tippain (VAS)was lower in Group Acompared to GroupB at alltime intervals in the postoperative period. This difference was statistically significant at 36 hrs and 72hrs in the postoperative period (p = 0.05) ( Table 3). The mean (VAS in cm) intensity of individual pain component ie parietal, visceraland shoulder tip pain are shown in Fig 3. The time from extubation to the administration of first dose of tramadol was significantly longer in Group A (189.30± 152.28 min versus 122.30± 88.46 min Group B) (p=0.045). Both frequency and total consumptionof tramadolwere significantlyless inGroup A (p=0.00). Thenumber of patients requiringsecond rescueanalgesia, the difference in the frequency of administration and totaldose of second rescue analgesia requirement was similar in both the groups. The second rescue analgesia(intravenous pethidine) was given in 5 patients (12.5%) ofGroupAversus 11patients (27.5%) in Group B (p=0.08). From extubation, the time of administration of second analgesia was 677.00± 185.93   Table 3).
The incidence of nausea was 27.5% in Group A and 51.2% in Group B (p=0.05). In Group A,7 (17.5%) patients had vomiting, while in Group B, 8 (20.5%) patients complained of vomiting in the postoperative period (p=0.95). Rescue antiemetics were given to 7 patientsin GroupAand 13 patientsin Group B.No adverse effects were noted in any of the participants related to anaesthetic interventions. All the participants were satisfied with the anesthetic technique used.

Discussion
Living donor nephrectomies are routinely being performed for last fiveyears in our institute, thus fulfilling one of the basic criteria for design of perioperative analgesia trials. In the present study, two groups had similar demographic profile, perioperative hemodynamicparameters andother intraoperativevariables like the duration of pneumoperitoneum, end tidal carbon dioxide concentration, surgery and anaesthesia time. As reported in the literature 5, 7-11 , the intensity of parietal pain perceived was more than visceral pain and pain used to aggravate during movement and coughing. However,we found consistently lower parietaland visceralpain scores and the incidence of shoulder pain was reduced to one fourth in Group A compared to Group B. This difference in pain scores can be attributed to the analgesic regimen used.
Previously, reduction in parietal pain scores have beendemonstrated by local anaestheticsinfiltration into the laparoscopic incision sites in laparoscopic cholecystectomy, appendicectomy, gynecologic or urological laparoscopy patients. 5,7,[17][18][19] However, the literature is notuniform on this aspect with severalstudies failing to show a significant effect. 20,21 In a systematic review, Moiniche et al 20 found no evidence ofany measurable effect of port site infiltration with local anaesthetics on postoperative pain. In the present study, at the completion ofprocedure, allthe patients received bupivacaine infiltration (15ml of 0.25%) at surgical incision/port sites. But,Group Bpatients perceivedsignificantly more pain, even duringrest. There was a significant difference in median VAS on movement and coughingat 30 minutes, 4 hour, 8 hour and 12 hour of postoperative period.Thus, trocar site infiltration alone was not found to be effective for postoperative pain management. Another analgesicmodality usedin thetreatment group was intraperitoneal saline irrigation for removal of residualcarbon dioxide and bupivacaine instillation into the operated renal fossa. It has been reported that this maneuversignificantly reducespostoperative analgesic requirements. 13,,18,22-27 Recently, Boddy et al 12 conducted ameta-analysis of the 24randomized controlled trials to establish the safety and efficacy of intraperitoneal localanaesthesia in laparoscopic cholecystectomies. The drugwas administered after the surgical dissection in fifteen trials and in another six studies, local anaesthetics were instilled both before and after the establishmentof pneumoperitoneum.Authors suggested that localanaesthetics may be more effective if at least some of it is instilled before any surgicaldissection. In present study, significant improvement in pain scores was noticed in the first 12 hours only. Further reduction inpost-laparoscopic painmight have been achieved by preemptive administration of localanaesthetics. Future studies can be conducted to establish this fact in laparoscpic donor nephrectomies.
Patients in multimodalanalgesia group also received orogastric acetazolamide 13 , a carbonic anhydrase inhibitor which decreases the rate of formation of H + ion and can retard peritoneal acidification re- sponsible fo r visceral and referred pain after laparoscopy. Harvey et al 14 investigated the effect of intravenous acetazolamide (5mg.kg -1 ) on post laparoscopic cholecystectomy pain and found that intravenous acetazolamide given just after induction of anesthesia reduces the referred pain in the initial postoperative period. In a previous study conducted in our institute (Bala I etal. Personal Communication), oral acetazolamide was administered two hours prior to laparoscopic cholecystectomy, incidence of STP was 35% in the control group, 15% in the acetazolamide group and 10% in the saline irrigation group. As IV preparation of the drug was not available in India and the bioavailability of drugis 100% even after oral use 13 , acetazolamide was administered via the orogastric route, just after the induction of anaesthesia.Using this technique concomitant with intraperitonealsaline irrigation and bupivacaineinstillation reducedreferred pain in multimodalanalgesia group patients to 7.5% (72 hours observation period) thoughthe durationof pneumoperitoneum was more than two times in LDN patients compared to laparoscopic cholecystectomy surgery. The reported incidence of shoulder tip pain is 35-63% afterlaparoscopic sterilization 17 and 30-45% post laparoscopic cholecystectomy 14-21, 22, when patients were evaluated for 24-48 hours. Bisgaard et al observed an incidence of 38-66% in first week and 21-25 % in 4 th week after laparoscopic Nissen fundoplication. 28 However, there is paucity of data on the incidence of shoulder tip pain after laparoscopic renalsurgeries. Keepingin mind, the nature of surgery and associated reduction in renalblood flow by pneumoperitoneum (which can predispose healthy renal donors to the postoperative risk of acute renal failure),intravenous tramadol was used to meet additional analgesia requirements and administration NSAID's drugs was avoided. The time intervalfor the first dose of rescue analgesiaadministration was longer and total analgesic consumption was reduced in multimodalanalgesia group.
Though present study is not adequately powered to detect drug-related side effects, none of the participants had adverse effects related to the study drugs (bupivacaine and acetazolamide). Sundaram et al 29 performed a retrospective chart review for 253 laparoscopic live donors. The overall rate of complications in the investigated series was 10.3%. Three of their patients required reexploration for postoperative bleeding. In the present study, re-exploration was required in one of the participants where it was found that a weck clip had partially slipped from a gonadal vessel. This patient was excluded from the data analysis because repeat surgery potentially confounds postoperative pain. No other surgicalcomplications were noted.Allthe allograftsfunctionedwellimmediately after the surgery. There were no readmissions.
In conclusion, a multimodalanalgesic approach provides betterpostoperative pain relief afterLDN. This includesa combinationof orogastricacetazolamide, intraperitoneal saline irrigation anduse ofbupivacaine in the operated renal fossa, pfannenstiel incision and laparoscopic port sites. Further large randomized trials are indicated to determine the cost-effectiveness and adverse event profile ofthis combinedanalgesia modality inlaparoscopic donornephrectomy surgeries.